PB1909: LOW-BURDEN TP53 MUTATIONS REPRESENT FREQUENT GENETIC EVENTS IN CLL WITH AN INCREASED RISK FOR TREATMENT INITIATION
Authors: Tamás László, Lili Kotmayer, Lajos Hegyi, Stefánia Gróf, Béla Kajtár, Alexandra Balogh, Júlia Weisinger, Tamás Masszi, Zsolt Nagy, Judit Demeter, Péter Farkas, Ildikó Istenes, Róbert Szász, Lajos Gergely, Adrienn Sulák, Zita Borbényi, Dóra Lévai, Tamás Schneider, Erika Szaleczky, Piroska Pettendi, Emese Bodai, László Szerafin, László Rejtő, Árpád Bátai, Mária Ágnes Dömötör, Hermina Sánta, Márk Plander, Tamás Szendrei, Péter Ilonczai, Aryan Hamed, Zsolt Lázár, Zsolt Pauker, Gáspár Radványi, Adrienn Kiss, Gábor Körösmezey, János Jakucs, Péter János Dombi, Zsófia Simon, Zsolt Klucsik, Mihály Gurzó, Márta Tiboly, Tímea Vidra, András Bors, Hajnalka Andrikovics, Miklós Egyed, Tamás Székely, András Masszi, András Matolcsy, Donát Alpár, Csaba Bödör
Journal: HemaSphere (2023)

Topic: 5. Chronic lymphocytic leukemia and related disorders - Biology & Translational Research Background: Presence of TP53 mutations and/or deletions of chromosomal region 17p (del(17p)) represent established prognostic and predictive biomarkers for chronic lymphocytic leukemia (CLL). However, the clinical significance of low-burden TP53 variants (variant allele frequency: <10%) is still a matter of debate, with some studies suggesting a reporting threshold below 10%. Aims: In this study, we aimed to scrutinize the subclonal architecture and clinical impact of TP53 mutations using a sensitive, next-generation sequencing-based (NGS) mutation analysis in a ‘real-world’ cohort of Hungarian CLL patients. Methods: Peripheral blood samples from 901 patients with CLL were collected from 20 oncohematological centers in Hungary. TP53 mutations were screened using Multiplicom SureMASTR TP53 Panel (Agilent, Santa Clara, CA, USA) covering the whole coding sequence of the TP53 gene. All TP53 variants below the 10% cut-off value were validated by either an alternative TP53 NGS panel (CleanPlex, Paragon Genomics, CA, USA) or by droplet digital polimerase chain reaction (ddPCR). The del(17p) status was screened as part of the routine diagnostic characterization by interphase fluorescence in situ hybridisation (FISH). Kaplan-Meier-survival curves and log rank tests were performed to compare survival times between different patient subgroups. Results: In 17.6% (159/901) of the patients we identified 226 TP53 mutations, with 49% (n=110) of those being high-burden variants, and 51% (n=116) representing low-burden mutations. Low-burden TP53 mutations as sole alterations were identified in 39% (n=62) of all mutated cases with 82.3% (51/62) of these being represented by a single low-burden TP53 mutation. While both high- and low-burden TP53 mutations appeared in most cases as sole alterations (39.6%, (63/159) and 32.1% (51/159) respectively), multiple mutations could be detected in 28.3% (45/159) of TP53 mutated cases showing heterogenous subclonal composition. As for the the entire patient cohort, 67.7% (153/226) of the detected TP53 mutations were validated by either NGS or ddPCR. All low-burden mutations examined between 5-10% variant allele frequency were successfully validated (n=38), while 74.3% (78/105) of the TP53 mutations with variant allele frequencies between 1-5% could be confirmed. Considering samples collected exclusively prior to first treatment initiation, we found significant differences in time to first treatment (TTFT) between patients harbouring either high-burden or low-burden TP53 mutations versus wild-type patients (high-burden vs wild type TP53: p<0.0001; low-burden vs wild type TP53: p=0.0031). Considering IGHV mutational status, patients with unmutated IGHV harbouring TP53 mutation showed significantly lower TTFT compared to patients with wild-type TP53 regardless of the IGHV status. Summary/Conclusion: In this study, we explored the repertoire and clinical impact of low-burden TP53 mutations in a nation-wide, ’real world’ Hungarian patient cohort. Our results demonstrate that patients with sole low-burden TP53 mutations represent more than one third of patients with TP53 mutations, having significantly increased risk for treatment initiation. Furthermore, our data demonstrates that TP53 variants between the 5-10% variant allele frequency range can be reliably detected by NGS, hence the 10% cut-off value for TP53 variant reporting in routine diagnostics might be worth reconsidering. Keywords: B cell chronic lymphocytic leukemia, Prognostic, TP53